Sensorineuronal hearing loss (SNHL), also called “nerve deafness,” is a significant communication problem that affects tens of millions of people in the U.S. alone. Loss of the inner ear sensory hair cells that detect sound is thought to be a major cause of this deficit. The anatomy of the inner ear is well known to those of ordinary skill in the art (see, e.g., Gray's Anatomy, Revised American Edition (1977), pages 859-867, incorporated herein by reference). In brief, the inner ear includes three sensory portions: the cochlea, which senses sound; the semicircular canals, which sense angular acceleration; and the otolithic organs, which sense linear acceleration. In each of these sensory portions, specialized sensory hair cells are arrayed upon one or more layers of inner ear supporting cells. Supporting cells underlie, at least partially surround, and physically support sensory hair cells within the inner ear. In operation, the sensory hair cells are physically deflected in response to sound or motion, and their deflection is transmitted to nerves which send nerve impulses to the brain for processing and interpretation.
In mammals, the inner ear is normally incapable of regenerating damaged or dead inner ear sensory hair cells. Thus, hearing disorders that result from the death or deterioration of sensory hair cells typically result in a permanent hearing impairment. Sensorineuronal hearing loss can be caused by a multitude of events including age-related loss (presbycusis), noise exposure, drug exposure (e.g., antibiotics and anti-cancer therapeutics), infections, genetic mutations (syndromic and non-syndromic) and autoimmune disease.
Currently, the treatment for acquired sensorineuronal hearing loss involves the use of external hearing aids and cochlear implants. Both devices have rather limited therapeutic potential and more importantly, do not address the problem of restoring structure or function to the auditory sensory epithelium.
A more recent approach to the problem of regenerating sensory inner ear hair cells is disclosed in published international application serial number PCT/US99/24829 which discloses methods for stimulating the regeneration of inner ear cells (including sensory hair cells) that include the step of introducing into inner ear cells nucleic acid molecules that encode a transcription factor capable of stimulating the regeneration of inner ear cells.
The present inventors have discovered that destruction of existing inner ear sensory hair cells promotes the re-entry of normally quiescent inner ear supporting cells (that express reduced levels of one or more cell cycle inhibitor proteins, or in which cell cycle protein activity has been reduced) into the cell cycle to yield progeny cells that can be induced to form inner ear sensory hair cells, as disclosed herein. In some instances, destruction of existing inner ear sensory hair cells is sufficient to stimulate underlying and/or surrounding inner ear support cells to develop into sensory hair cells. In other instances, efficient regeneration of sensory hair cells from support cells requires destruction of existing inner ear sensory hair cells in combination with at least one other stimulus, as described herein. Additionally, the present inventors have discovered that stimulating the proliferation of inner ear support cells (with or without stimulating the regeneration of inner ear sensory hair cells) improves the auditory function of the inner ear.